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All Articles in Genetic Phenomena

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201 full-text articles. Page 1 of 8.

A Rationally Engineered Capsid Variant Of Aav9 For Systemic Cns-Directed And Peripheral Tissue-Detargeted Gene Delivery In Neonates, Dan Wang, Shaoyong Li, Dominic J. Gessler, Jun Xie, Li Zhong, Jia Li, Karen Tran, Kim Van Vliet, Lingzhi Ren, Qin Su, Ran He, Jason E. Goetzmann, Terence R. Flotte, Mavis Agbandje-McKenna, Guangping Gao 2018 University of Massachusetts Medical School

A Rationally Engineered Capsid Variant Of Aav9 For Systemic Cns-Directed And Peripheral Tissue-Detargeted Gene Delivery In Neonates, Dan Wang, Shaoyong Li, Dominic J. Gessler, Jun Xie, Li Zhong, Jia Li, Karen Tran, Kim Van Vliet, Lingzhi Ren, Qin Su, Ran He, Jason E. Goetzmann, Terence R. Flotte, Mavis Agbandje-Mckenna, Guangping Gao

Open Access Articles

Adeno-associated virus (AAV) has provided the gene therapy field with the most powerful in vivo gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9's capability to traverse the blood-brain barrier and transduce neurons. This variant shows reduced transduction in peripheral tissues when delivered through ...


The Effect Of Diet On Craniofacial Growth In Osteogenesis Imperfecta Mouse Model, Summer H. Ladd 2018 University of North Texas Health Science Center at Fort Worth

The Effect Of Diet On Craniofacial Growth In Osteogenesis Imperfecta Mouse Model, Summer H. Ladd

Theses and Dissertations

Osteogenesis imperfecta (OI, or “brittle bone disease”) is a rare disorder that is caused by genetic point mutations (COL1A1/COL1A2) that affect type 1 collagen. In OI type III (severe) patients, limb bones are more susceptible to skeletal fractures and the bones of the craniofacial region are underdeveloped. Some OI type III patients also suffer from dental malocclusions or fractures (dentinogenesis imperfecta, DI). The goals of this project are 1) to describe the facial phenotype in an OI mouse model, to see if this model can be used to test potential behavioral and pharmaceutical interventions; and 2) to determine if ...


Effect Of Trinucleotide Repeats In The Huntington's Gene On Intelligence, Jessica K. Lee, Amy Conrad, Eric Epping, Kathy Mathews, Vincent Magnotta, Jeffrey D. Dawson, Peg Nopoulos 2018 University of Iowa

Effect Of Trinucleotide Repeats In The Huntington's Gene On Intelligence, Jessica K. Lee, Amy Conrad, Eric Epping, Kathy Mathews, Vincent Magnotta, Jeffrey D. Dawson, Peg Nopoulos

Stead Family Department of Pediatrics Publications

BACKGROUND: Huntington's Disease (HD) is caused by an abnormality in the HTT gene. This gene includes trinucleotide repeats ranging from 10 to 35, and when expanded beyond 39, causes HD. We previously reported that CAG repeats in the normal range had a direct and beneficial effect on brain development with higher repeats being associated with higher cognitive function. The current study now expands this line of inquiry to evaluate the effects of CAG repeat throughout the entire spectrum of repeats from 15 to 58.

METHODS: We evaluated brain function in children ages 6-18 years old. DNA samples were processed ...


Surfactant Deficiency Syndrome In An Infant With A C-Terminal Frame Shift In Abca3: A Case Report, Nour Akil, Anthony J. Fischer 2018 University of Iowa

Surfactant Deficiency Syndrome In An Infant With A C-Terminal Frame Shift In Abca3: A Case Report, Nour Akil, Anthony J. Fischer

Stead Family Department of Pediatrics Publications

Deficiency in ATP binding cassette A3 (ABCA3) causes neonatal respiratory distress, hypoxemic respiratory failure, and interstitial lung disease. ABCA3 transports phospholipids into the lamellar bodies of type II alveolar cells, a critical step in alveolar surfactant production. We report a term infant with ABCA3 surfactant deficiency syndrome with the E292V (c.875A>T; p.Glu292Val) mutation in trans with a novel C-terminal frame shift mutation (c.4938delC; p.Met1647fs). This mutation removes the final 58 amino acids and substitutes 33 incorrect amino acids. The frame shift spares membrane spanning and nucleotide binding domains, but disrupts a highly conserved C-terminal domain ...


Dystrophic Calcifications Point The Way-Unusual And Early Diagnostic Clue Of Conradi-Hünermann-Happle Syndrome, Kenneth Yu, Alexander T. Reid, Stephanie J T Chen, Rajiv M. Patel, Steven M. Donn, Johann E. Gudjonsson, Lori Lowe 2018 University of Iowa

Dystrophic Calcifications Point The Way-Unusual And Early Diagnostic Clue Of Conradi-Hünermann-Happle Syndrome, Kenneth Yu, Alexander T. Reid, Stephanie J T Chen, Rajiv M. Patel, Steven M. Donn, Johann E. Gudjonsson, Lori Lowe

Stead Family Department of Pediatrics Publications

No abstract provided.


Bayesian Nonparametric Discovery Of Isoforms And Individual Specific Quantification, Derek Aguiar, Li-Fang Cheng, Bianca Dumitrascu, Fantine Mordelet, Athma A. Pai, Barbara E. Engelhardt 2018 Princeton University

Bayesian Nonparametric Discovery Of Isoforms And Individual Specific Quantification, Derek Aguiar, Li-Fang Cheng, Bianca Dumitrascu, Fantine Mordelet, Athma A. Pai, Barbara E. Engelhardt

Open Access Articles

Most human protein-coding genes can be transcribed into multiple distinct mRNA isoforms. These alternative splicing patterns encourage molecular diversity, and dysregulation of isoform expression plays an important role in disease etiology. However, isoforms are difficult to characterize from short-read RNA-seq data because they share identical subsequences and occur in different frequencies across tissues and samples. Here, we develop BIISQ, a Bayesian nonparametric model for isoform discovery and individual specific quantification from short-read RNA-seq data. BIISQ does not require isoform reference sequences but instead estimates an isoform catalog shared across samples. We use stochastic variational inference for efficient posterior estimates and ...


Identification Of Epigenetic Regulators Of Dux4-Fl For Targeted Therapy Of Facioscapulohumeral Muscular Dystrophy, Charis L. Himeda, Takako I. Jones, Ching-Man A. Virbasius, Lihua Julie Zhu, Michael R. Green, Peter L. Jones 2018 University of Massachusetts Medical School

Identification Of Epigenetic Regulators Of Dux4-Fl For Targeted Therapy Of Facioscapulohumeral Muscular Dystrophy, Charis L. Himeda, Takako I. Jones, Ching-Man A. Virbasius, Lihua Julie Zhu, Michael R. Green, Peter L. Jones

Open Access Articles

Facioscapulohumeral muscular dystrophy (FSHD) is caused by epigenetic de-repression of the disease locus, leading to pathogenic misexpression of the DUX4 gene in skeletal muscle. While the factors and pathways involved in normal repression of the FSHD locus in healthy cells have been well characterized, very little is known about those responsible for the aberrant activation of DUX4-fl in FSHD myocytes. Reasoning that DUX4-fl activators might represent useful targets for small molecule inhibition, we performed a highly targeted, candidate-based screen of epigenetic regulators in primary FSHD myocytes. We confirmed several of the strongest and most specific candidates (ASH1L, BRD2, KDM4C, and ...


Micro Rnas From Dna Viruses Are Found Widely In Plasma In A Large Observational Human Population, Milka Koupenova-Zamor, Eric O. Mick, Heather A. Corkrey, Tianxiao Huan, Lauren Clancy, Ravi Shah, Emelia J. Benjamin, Daniel Levy, Evelyn A. Kurt-Jones, Kahraman Tanriverdi, Jane E. Freedman 2018 University of Massachusetts Medical School

Micro Rnas From Dna Viruses Are Found Widely In Plasma In A Large Observational Human Population, Milka Koupenova-Zamor, Eric O. Mick, Heather A. Corkrey, Tianxiao Huan, Lauren Clancy, Ravi Shah, Emelia J. Benjamin, Daniel Levy, Evelyn A. Kurt-Jones, Kahraman Tanriverdi, Jane E. Freedman

Open Access Articles

Viral infections associate with disease risk and select families of viruses encode miRNAs that control an efficient viral cycle. The association of viral miRNA expression with disease in a large human population has not been previously explored. We sequenced plasma RNA from 40 participants of the Framingham Heart Study (FHS, Offspring Cohort, Visit 8) and identified 3 viral miRNAs from 3 different human Herpesviridae. These miRNAs were mostly related to viral latency and have not been previously detected in human plasma. Viral miRNA expression was then screened in the plasma of 2763 participants of the remaining cohort utilizing high-throughput RT-qPCR ...


Haplotype Analysis Of Apoe Intragenic Snps, Vladimir N. Babenko, Dmitry A. Afonnikov, Elena V. Ignatieva, Anton V. Klimov, Fedor E. Gusev, Evgeny I. Rogaev 2018 Novosibirsk State University

Haplotype Analysis Of Apoe Intragenic Snps, Vladimir N. Babenko, Dmitry A. Afonnikov, Elena V. Ignatieva, Anton V. Klimov, Fedor E. Gusev, Evgeny I. Rogaev

Open Access Articles

BACKGROUND: APOE epsilon4 allele is most common genetic risk factor for Alzheimer's disease (AD) and cognitive decline. However, it remains poorly understood why only some carriers of APOE epsilon4 develop AD and how ethnic variabilities in APOE locus contribute to AD risk. Here, to address the role of APOE haplotypes, we reassessed the diversity of APOE locus in major ethnic groups and in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset on patients with AD, and subjects with mild cognitive impairment (MCI), and control non-demented individuals.

RESULTS: We performed APOE gene haplotype analysis for a short block of five SNPs ...


Effects Of Larval Density On Gene Regulation In Caenorhabditis Elegans During Routine L1 Synchronization, Io Long Chan, Oliver J. Rando, Colin C. Conine 2018 University of Massachusetts Medical School

Effects Of Larval Density On Gene Regulation In Caenorhabditis Elegans During Routine L1 Synchronization, Io Long Chan, Oliver J. Rando, Colin C. Conine

University of Massachusetts Medical School Faculty Publications

Bleaching gravid C. elegans followed by a short period of starvation of the L1 larvae is a routine method performed by worm researchers for generating synchronous populations for experiments. During the process of investigating dietary effects on gene regulation in L1 stage worms by single-worm RNA-Seq, we found that the density of resuspended L1 larvae affects expression of many mRNAs. Specifically, a number of genes related to metabolism and signalling are highly expressed in worms arrested at low density, but are repressed at higher arrest densities. We generated a GFP reporter strain based on one of the most density-dependent genes ...


Biochemical Analysis Of Dimethyl Suberimidate-Crosslinked Yeast Nucleosomes, Yuichi Ichikawa, Paul D. Kaufman 2018 University of Massachusetts Medical School

Biochemical Analysis Of Dimethyl Suberimidate-Crosslinked Yeast Nucleosomes, Yuichi Ichikawa, Paul D. Kaufman

Open Access Articles

Nucleosomes are the fundamental unit of eukaryotic chromosome packaging, comprised of 147 bp of DNA wrapped around two molecules of each of the core histone proteins H2A, H2B, H3, and H4. Nucleosomes are symmetrical, with one axis of symmetry centered on the homodimeric interaction between the C-termini of the H3 molecules. To explore the functional consequences of nucleosome symmetry, we designed an obligate pair of H3 heterodimers, termed H3X and H3Y, allowing us to compare cells with single or double H3 alterations. Our biochemical validation of the heterodimeric X-Y interaction included intra-nucleosomal H3 crosslinking using dimethyl suberimidate (DMS). Here, we ...


A Parental Requirement For Dual-Specificity Phosphatase 6 In Zebrafish, Jennifer M. Maurer, Charles G. Sagerstrom 2018 University of Massachusetts Medical School

A Parental Requirement For Dual-Specificity Phosphatase 6 In Zebrafish, Jennifer M. Maurer, Charles G. Sagerstrom

Open Access Articles

BACKGROUND: Signaling cascades, such as the extracellular signal-regulated kinase (ERK) pathway, play vital roles in early vertebrate development. Signals through these pathways are initiated by a growth factor or hormone, are transduced through a kinase cascade, and result in the expression of specific downstream genes that promote cellular proliferation, growth, or differentiation. Tight regulation of these signals is provided by positive or negative modulators at varying levels in the pathway, and is required for proper development and function. Two members of the dual-specificity phosphatase (Dusp) family, dusp6 and dusp2, are believed to be negative regulators of the ERK pathway and ...


Editing Out Five Serpina1 Paralogs To Create A Mouse Model Of Genetic Emphysema, Florie Borel, Huaming Sun, Marina Zieger, Andrew Cox, Brynn Cardozo, Weiying Li, Gabriella Oliveira, Airiel Davis, Alisha Gruntman, Terence R. Flotte, Michael H. Brodsky, Andrew M. Hoffman, Mai K. Elmallah, Christian Mueller 2018 University of Massachusetts Medical School

Editing Out Five Serpina1 Paralogs To Create A Mouse Model Of Genetic Emphysema, Florie Borel, Huaming Sun, Marina Zieger, Andrew Cox, Brynn Cardozo, Weiying Li, Gabriella Oliveira, Airiel Davis, Alisha Gruntman, Terence R. Flotte, Michael H. Brodsky, Andrew M. Hoffman, Mai K. Elmallah, Christian Mueller

Pediatric Publications and Presentations

Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is alpha-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully generated until now. Here we create a quintuple Serpina1a-e knockout using CRISPR/Cas9-mediated genome editing. The phenotype recapitulates the human disease phenotype, i.e., absence of hepatic and circulating AAT translates functionally to a reduced capacity to inhibit neutrophil elastase. With age, Serpina1 null mice develop emphysema spontaneously, which can be induced in younger mice ...


Cbx4 Sumoylates Prdm16 To Regulate Adipose Tissue Thermogenesis, Qingbo Chen, Lei Huang, Dongning Pan, Lihua (Julie) Zhu, Yong-Xu Wang 2018 University of Massachusetts Medical School

Cbx4 Sumoylates Prdm16 To Regulate Adipose Tissue Thermogenesis, Qingbo Chen, Lei Huang, Dongning Pan, Lihua (Julie) Zhu, Yong-Xu Wang

Open Access Articles

Transcriptional co-activator Prdm16 controls brown fat development and white fat browning, but how this thermogenic function is modulated post-translationally is poorly understood. Here, we report that Cbx4, a Polycomb group protein, is a SUMO E3 ligase for Prdm16 and that Cbx4-mediated sumoylation of Prdm16 is required for thermogenic gene expression. Cbx4 expression is enriched in brown fat and is induced in adipose tissue by acute cold exposure. Sumoylation of Prdm16 at lysine 917 by Cbx4 blocks its ubiquitination-mediated degradation, thereby augmenting its stability and thermogenic function. Moreover, this sumoylation event primes Prdm16 to be further stabilized by methyltransferase Ehmt1. Heterozygous ...


Myc Amplification In Subtypes Of Breast Cancers In African American Women, Tammey J. Naab, Anita Gautam, Luisel Ricks-Santi, Ashwini K. Esnakula, Yasmine M. Kanaan, Robert L. DeWitty, Girmay Asgedom, Khepher H. Makambi, Massih Abawi, Jan K. Blancato 2018 Howard University

Myc Amplification In Subtypes Of Breast Cancers In African American Women, Tammey J. Naab, Anita Gautam, Luisel Ricks-Santi, Ashwini K. Esnakula, Yasmine M. Kanaan, Robert L. Dewitty, Girmay Asgedom, Khepher H. Makambi, Massih Abawi, Jan K. Blancato

Open Access Articles

BACKGROUND: MYC overexpression is associated with poor prognosis in breast tumors (BCa). The objective of this study was to determine the prevalence of MYC amplification and associated markers in BCa tumors from African American (AA) women and determine the associations between MYC amplification and clinico-pathological characteristics.

METHODS: We analyzed 70 cases of well characterized archival breast ductal carcinoma specimens from AA women for MYC oncogene amplification. Utilizing immune histochemical analysis estrogen receptor (ER), progesterone receptor (PR), and (HER2/neu), were assessed. Cases were Luminal A (ER or PR+, Ki-67 < 14%), Luminal B (ER or PR+, Ki-67 = > 14% or ER or PR+ HER2+), HER2 (ER-, PR-, HER2+), and ...


The Cjun Nh2-Terminal Kinase (Jnk) Pathway Contributes To Mouse Mammary Gland Remodeling During Involution, Nomeda A. Girnius, Yvonne J. K. Edwards, Roger J. Davis 2018 University of Massachusetts Medical School

The Cjun Nh2-Terminal Kinase (Jnk) Pathway Contributes To Mouse Mammary Gland Remodeling During Involution, Nomeda A. Girnius, Yvonne J. K. Edwards, Roger J. Davis

University of Massachusetts Medical School Faculty Publications

Involution returns the lactating mammary gland to a quiescent state after weaning. The mechanism of involution involves collapse of the mammary epithelial cell compartment. To test whether the cJUN NH2-terminal kinase (JNK) signal transduction pathway contributes to involution, we established mice with JNK deficiency in the mammary epithelium. We found that JNK is required for efficient involution. JNK deficiency did not alter the STAT3/5 or SMAD2/3 signaling pathways that have been previously implicated in this process. Nevertheless, JNK promotes the expression of genes that drive involution, including matrix metalloproteases, cathepsins, and BH3-only proteins. These data demonstrate that JNK ...


Fundamental Limits On Dynamic Inference From Single-Cell Snapshots, Caleb Weinreb, Samuel Wolock, Betsabeh K. Tusi, Merav Socolovsky, Allon M. Klein 2018 Harvard Medical School

Fundamental Limits On Dynamic Inference From Single-Cell Snapshots, Caleb Weinreb, Samuel Wolock, Betsabeh K. Tusi, Merav Socolovsky, Allon M. Klein

Open Access Articles

Single-cell expression profiling reveals the molecular states of individual cells with unprecedented detail. Because these methods destroy cells in the process of analysis, they cannot measure how gene expression changes over time. However, some information on dynamics is present in the data: the continuum of molecular states in the population can reflect the trajectory of a typical cell. Many methods for extracting single-cell dynamics from population data have been proposed. However, all such attempts face a common limitation: for any measured distribution of cell states, there are multiple dynamics that could give rise to it, and by extension, multiple possibilities ...


Alpha Cell Function And Gene Expression Are Compromised In Type 1 Diabetes, Marcela Brissova, David Blodgett, Dale L. Greiner, David M. Harlan, Alvin C. Powers 2018 Vanderbilt University Medical Center

Alpha Cell Function And Gene Expression Are Compromised In Type 1 Diabetes, Marcela Brissova, David Blodgett, Dale L. Greiner, David M. Harlan, Alvin C. Powers

Open Access Articles

Many patients with type 1 diabetes (T1D) have residual beta cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual beta cells and alpha cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant beta cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D alpha cells was markedly reduced, and these cells had alterations in transcription factors constituting alpha and ...


Cerebral Organoids Derived From Sandhoff Disease-Induced Pluripotent Stem Cells Exhibit Impaired Neurodifferentiation, Maria L. Allende, Emily K. Cook, Bridget C. Larman, Adrienne Nugent, Jacqueline M. Brady, Diane Golebiowski, Miguel Sena-Esteves, Cynthia J. Tifft, Richard L. Proia 2018 National Institutes of Health

Cerebral Organoids Derived From Sandhoff Disease-Induced Pluripotent Stem Cells Exhibit Impaired Neurodifferentiation, Maria L. Allende, Emily K. Cook, Bridget C. Larman, Adrienne Nugent, Jacqueline M. Brady, Diane Golebiowski, Miguel Sena-Esteves, Cynthia J. Tifft, Richard L. Proia

Open Access Articles

Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of beta-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease ...


Dznep Inhibits H3k27me3 Deposition And Delays Retinal Degeneration In The Rd1 Mice, Shijie Zheng, Lirong Xiao, Yu Liu, Yujiao Wang, Lin Cheng, Junjun Zhang, Naihong Yan, Danian Chen 2018 Sichuan University

Dznep Inhibits H3k27me3 Deposition And Delays Retinal Degeneration In The Rd1 Mice, Shijie Zheng, Lirong Xiao, Yu Liu, Yujiao Wang, Lin Cheng, Junjun Zhang, Naihong Yan, Danian Chen

Open Access Articles

Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases causing progressive loss of photoreceptors. Numerous gene mutations are identified to be related with RP, but epigenetic modifications may also be involved in the pathogenesis. Previous studies suggested that both DNA methylation and histone acetylation regulate photoreceptor cell death in RP mouse models. However, the role of histone methylation in RP has never been investigated. In this study, we found that trimethylation of several lysine sites of histone H3, including lysine 27 (H3K27me3), increased in the retinas of rd1 mice. Histone methylation inhibitor DZNep significantly reduced the calpain activity ...


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